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OVERVIEW OF INFLAMMATION
Inflammation
Ability to get rid of damage or necrotic tissues and foreign
invaders.
host response
a protective response designed to rid the organism of both
the
a.
initial cause of the cell injury (microbes, toxins) and the
b.
consequences of such injury
cardinal signs of inflammation:
1.
rubor
2.
tumor
3.
calor
4.
dolor
fifth clinical sign: function lasea (loss of function)
KEYPOINTS FOR INFLAMMATION
rapid onset
of short duration
of longer duration
associated with
a.
the
presence
of
lymphocytes
and
macrophage
b.
the proliferation of blood vessels
c.
fibrosis
d.
tissue destruction
Inflammation is terminated when the offending agent is
eliminated
The inflammatory response is closely intertwined with the
process of repair
Repair begins during inflammation but reaches completion
after the injurious influence has been neutralized.
The injured tissue is
a.
replaced through regeneration of native parenchymal
cell by
b.
filling of the defect with fibrous tissue (scarring)
c.
combination of both
Inflammation may be harmful in some situations
Inflammation may contribute to a variety of disease that are
not thought to be primarily due to abnormal host responses.
INFLAMMATION
FIVE CLASSICAL SIGNS
1. Changes in Blood Flow
Mechanism
o
Release of vasoactive peptides from damaged and
aggregating cells
Clinical Response
2.
-
3.
-
4.
-
5.
-
o
redness
o
heat
Permeability Changes
Mechanism
o
contraction of lining cells
o
widening of endothelial junctions
o
fluid leakage
o
sensory nerve irritation
Clinical Response
o
swelling and pain
Hemostasis
Mechanism
o
Local concentration of blood in capillaries and
venules
o
congestion
o
decreased blood flow leads to hypoxia
Clinical response
o
loss of function
WBC responses
Chemotaxis
Mechanism of Action
o
neutrophils
o
mononuclear cells
Phagocytosis
Mechanism of Action
o
WBCs identify, attack, ingest and dispose foreign
matter
o
Enzyme, O2 radicals, inflammatory mediators
o
Removal of noxious agents, tissue debris and fibrin
leads to further tissue damage
cytoplasmic receptors
uric acid
DNA
Hypoxia - HIF-
c.
d.
-
Foreign bodies
elicit inflammation because they cause traumatic tissue
injury or carry microbes
immune reactions
hypersensitivity reactions
injurious immune response may be directed against
CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
Exudation
escape of fluid, proteins, and blood cells from the vascular
system into the interstitial tissue or body cavities
can involve:
a.
Exudate
o
extravascular
fluid
with
high
protein
concentration and cellular debris
o
high specific gravity-increased capillary
permeability
b.
Transudate
o
fluid with low protein content
o
low specific gravity
o
ultrafiltrate of blood plasma results from
osmotic or hydrostatic imbalance across the
vessel wall
Light criteria
pleural fluid/serum protein ration > 0.50
Pleural fluid/serum LD ration > 0.60
Pleural fluid LD >200 IU
Edema
denotes an excess of fluid in the interstitial tissue or serous
cavities
can be either an exudate or a transudate
Pus
a purulent exudate
rich in leukocytes (mostly neutrophils) and necrotic debris
Normal
Endothelial Injury
long-lived
Increased Transcytosis
occurs in venules
induced by VEGF
capable of phagocytosis
functions to
a.
ingest and kill bacteria and other microbes
b.
eliminate necrotic tissue and foreign substances
c.
produce growth factors that aid in repair
Leukocytes, when strongly activated, may induce tissue
damage and prolong inflammation (leukocyte products that
destroy microbes and necrotic tissues can also injure normal
host tissues
process involving leukocytes in inflammation consists of:
1.
recruitment from the blood into extravascular tissue
2.
recognition of microns and necrotic tissues
3.
removal of offending agent
the
CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
1.
2.
3.
has 3 types
o
L- selectin - leukocytes
o
E - selectin - endothelium
o
P - selectin - platelets and on endothelium
DIAPEDESIS
o
migration
of
leukocytes
through
the
endothelium
o
also known as transmigration
o
occurs mainly in post capillary venules
Several adhesion molecules present in the intercellular
junctions between the endothelial cells are involved in the
migration of leukocytes:
o
PECAM 1
o
junctional adhesion molecules
Genetic deficiencies in adhesion molecules
Major Role
Rolling
Rolling and Adhesion
Rolling
Adhesion,
Arrest,
transmigration
Adhesion
Chemotaxis of Leukocytes
Chemotaxis
o
leukocytes emigrate in tissues towards the site of
injury
o
locomotion originated along a chemical gradient
most
common
exogenous
agents
that
act
as
chemoattractant are bacteria products including:
a.
peptides that possess N-formylmethionine terminal
amino acid
b.
lipids
endogenous chemoattractant include:
a.
cytokines
b.
component of the complement system
c.
arachidonic acid metabolites
o
these chemotactic agents bind to specific seven
transmembrane G protein-coupled receptors on the
surface of leukocytes
o
signals from these receptors result in: activation of
2nd messengers that:
increase cytosolic Ca
CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
PAF
prostaglandins
leukotriene
o
binding of ligands to G protein-coupled receptors
induces
a.
migration of the cells from the blood through
the endothelium
b.
production of microbial substances by
activation of the respiratory burst
c.
Receptors for Opsonin
o
Opsonization - coating a particle to target for
ingestion.
o
substance for opsonization include:
a.
antibodies
b.
complement proteins
c.
lectins
o
Most efficient way: coating the particles with IgG
antibodies specific for particles
Phagocytosis
Engulfment
pseudopods
autoimmune disease
c.
Host
reacts
excessively
against
usually
harmless
environmental substance
allergy, asthma
-
acquired deficiencies
- Cell residents in tissues: MAST CELLS and TISSUE MACROPHAGE
CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
CELL-DERIVED MEDIATORS
1.
-
A.
Histamine
o
richest source of histamine are mast cells that are
normally present in the connective tissue adjacent
to blood vessels
o
also found in blood basophils and platelets
o
present in mast cell granules and is released by
mast cell degranulation in response to a variety of
stimuli including:
a.
physical injury
b.
binding of antibodies to mast cells
c.
fragments
of
complement
called
anaphylatoxins (C3a and C5a)
d.
histamine releasing proteins derived from
leukocytes
e.
neuropeptides
f.
cytokines
o
causes dilation of arterioles and increases the
permeability of venules
o
considered to be the principal mediator of the
immediate transient phase of increased vascular
permeability
Serotonin
o
5-hydroxytryptamine
o
present in platelets and neuroendocrine cells
o
release from platelets is stimulated when platelets
aggregate after contact with:
a.
thrombin
b.
collagen
c.
ADP
d.
antigen-antibody complex
o
platelet release reaction (key component of
coagulation) results in increased vascular
permeability
2.
-
Lipooxygenase - produce:
Leukotrienes
lipoxins
Cyclooxygenase
A.
Prostaglandins
o
produced by mast cells , macrophages, endothelial
cells and many other cell types
o
involved in the vascular and systemic reaction of
inflammation.
o
produced by the action of 2 cyclooxygenase:
a.
COX 1
b.
COX 2
most important PGs in inflammation are:
a.
PGE2
b.
PGD2
c.
PGF2
d.
PGI (prostacyclin)
e.
TXA2 (thromboxane)
TXA2 ( Thromboxane)
PGI2 (Prostacyclin)
vascular endothelium
vasodilator
potentiates
the
permeability
increasing
and
chemotactic effects of other mediators
PGD2
PGF2a
PGE2
hyperalgesic
converts
AA
to
5-hydroxyeicosatetraenoic
acid
(chemotactic
for
neutrophils;
precursor
for
Leukotrienes)
Leukotrienes are more potent than histamine in increasing
vascular permeability and causing bronchospasm
LTB4
causing
a.
aggregation and adhesion of the cells to venules
endothelium
b.
generation of ROS
c.
release of lysosomal enzymes
bronchospasm
B.
Lipoxins
o
o
o
o
o
CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
-
Cyclooxygenase inhibitors
o
aspirin, NSAIDS
o
inhibit both COX 1 and COX 2 inhibit
prostaglandin synthesis
Lipooxygenase inhibitor
o
5-lipooxygenase is not inhibited by NSAIDS
o
leukotriene production; block leukotriene receptors
Broad spectrum inhibitors (i.e. corticosteroids)
o
act by reducing the transcription genes encoding
COX-2,
phospholipase
A2,
proinflammatory
cytokines and iNOS
Fish oil
o
o
3.
4.
-
5.
-
6.
-
Tumor
platelets
basophils
mast cells
neutrophils
macrophages
endothelial cells
o
platelet aggregation
o
causes vasoconstriction and bronchoconstriction
o
at extremely low concentrations, it induces
vasodilation and increased venular permeability
with a potency 100 to 10000 times greater than
that of histamine.
o
also causes
a.
increased leukocyte adhesion to endothelial
cells
b.
Chemotaxis
c.
degranulation
d.
oxidative burst
o
can elicit most of the vascular and cellular
reactions of inflammation
o
boost synthesis of other mediators
REACTIVE OXYGEN SPECIES
endothelial cell damage with resultant increased vascular
permeability
injury to other cell types
inactivation of proteases
antioxidants include
1. superoxide dismutase
2. catalase
3. glutathione peroxidase
4. ceruloplasmin
5. iron free fraction of serum transferrin
NITRIC OXIDE
synthesized from L-arginine by the enzyme nitric oxide
synthase.
has dual actions in inflammation:
1. it relaxes vascular smooth muscle and promotes
vasodilation contributing to the vascular reaction
2. also an inhibitor of the cellular component of the
inflammatory response
NO also
a.
reduces platelet aggregation and adhesion
b. inhibits several features of mast cell-induced
inflammation and
c.
inhibits leukocyte recruitment.
production of enzymes
associated with
matrix remodeling
Inflammasome
mechanism:
a.
constitutively activate the inflammatory caspase
b.
interfere with negative regulation
CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
o
fractalkine
exist in 2 forms:
1.
cell surface bound protein can be induced on
endothelial cells by inflammatory cytokines promotes strong adhesion of monocyte and Tcell
2.
soluble form
Other Cytokines
A.
IL-6
8.
-
contain:
o
lysozyme
o
collagenase
o
gelatinase
o
lactoferrin
o
plasminogen activator
o
histaminase
o
alkaline phosphatase
b. larger azurophil granules
contain
o
myeloperoxidase
o
bacetiricidal factors
o
acid hydrolase
o
neutral protease
both types can fuse with phagocytic vacuoles
Acid protease
functions for
a.
transmission of pain signals
b. regulation of blood pressure
c.
stimulation of secretion by endocrine cells
d. increasing vascular permeability
of
an
anaphylatoxins
C5a
o
powerful chemotactic agent for neutrophils,
monocytes, eosinophils and basophils
o
activates lipooxygenase pathway of AA metabolism
further release of inflammatory mediators
2.
phagocytosis
Kinins
CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
Kallikrein
converts C5 to C5a
Factor XIIa
Note that:
2.
3.
Resolution
o
restoration of the site of acute inflammation
to normal
o
usual outcome when:
a.
the injury is short lived
b.
there has been little tissue destruction and
the
damaged
parenchymal
cells
can
regenerate.
also:
a.
clearance of injurious stimuli
b.
clearance of mediators and acute inflammatory
cells
c.
replacement of injured cells
d.
normal function
Healing by a connective tissue replacement (Fibrosis)
collagen deposition
loss of function
Progression of the response to chronic inflammation
SEROUS INFLAMMATION
-
FIBRINOUS INFLAMMATION
greater increase in vascular permeability large molecules
(i.e. fibrinogen) pass the vascular barrier, and fibrin is
formed and deposited in extracellular spaces.
Fibrinous exudate develops:
a.
when vascular leaks are large
b.
there is a local procoagulant stimulus
Fibrinous exudate is characteristic of inflammation in the
lining of body cavities, such as the meninges, pericardium
and pleura.
Fibrin appears as:
ULCERS
neutrophils
liquefactive necrosis
edema fluid
acute appendicitis
staphylococci
Abscesses
Abscesses have
outside
is
a
vascular
dilation
and
parenchymal and fibroblastic proliferation
(indicating chronic inflammation)
abscess may be walled off and replaced by connective tissue
CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
-
Ulcer
CHRONIC INFLAMMATION
-
implicated in cancer
3.
-
MORPHOLOGIC FEATURES
note that in acute inflammation, manifestation of AI include:
1.
vascular changes
2.
edema
3.
neutrophil infilitration
chronic inflammation is characterized by:
a.
infiltration with mononuclear cells
b.
tissue destruction induced by the persistent offending agent
or by the inflammatory cells
c.
attempts at healing by connective tissue replacement of
damaged tissue accomplished by angiogenesis and
fibrosis
ROLE OF MACROPHAGES IN CHRONIC INFLAMMATION
Macrophage
A.
CHAPTER 2
ACUTE AND CHRONIC INFLAMMATION
B.
-
C.
-
D.
E.
-
4. chills
5. anorexia
6. somnolence
7. malaise
SEPSIS
large amounts of organisms and LPS in the blood stimulate
the production of enormous quantities of several cytokines ,
TNF and IL-1
septic shock
DEFECTIVE INFLAMMATION
results in increased susceptibility to infection
associated with delayed wound healing
EXCESSIVE INFLAMMATION
Allergies
artherosclerosis
ischemic heart disease
Alzheimers disease
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